Amorphous hydrate of a cephalosporin antibiotic

ABSTRACT

A process for the preparation of cefdinir of the formula (I) the said process comprising the steps of: i) condensing 7-amino-3-cephem-4-carboxylic acid of the formula (XII) wherein R1 is as defined above with compound of the formula (XIII) in the presence of a tertiary amine and an organic solvent, followed by treatment with a base to produce a salt of compound formula (XIV), wherein M+ is a counter ion and ii) hydrolyzing the compound of the formula (XIV) using an acid in the presence of a solvent to produce cefdinir of formula (I).

FIELD OF THE INVENTION

The present invention relates to a novel amorphous hydrate of acephalosporin antibiotic. More particularly, the present inventionrelates to novel amorphous monohydrate of cefdinir of the formula (I).

The present invention also provides a process for the preparation of thenovel amorphous monohydrate of cefdinir of formula (I).

The present invention also provides new salts of compound of formula(XIV) and a process for the preparation of cefdinir using the new salts.

BACKGROUND OF THE INVENTION

Cefdinir is a third generation cephalosporin antibiotic for oraladministration and has a broader antibacterial spectrum over the generalgram positive and gram negative bacteria, especially againstStreptococci, than other antibiotics for oral administration.

In view of the vital antibiotic activities of cefdinir of the formula(I), various methods of preparation were reported. Cefdinir is for thefirst time claimed in U.S. Pat. No. 4,559,334 and the nature of theproduct that is disclosed in this patent is described as crystallinelike amorphous in subsequent US patent (U.S. Pat. No. 4,935,507). Thispatent also discloses a process for the preparation of cefdinir asdepicted in the Scheme I.

In the disclosed process, 7-amino-3-vinyl-3-cephem-4-carboxylic acidester where R represents a conventional carboxy protecting group, isacylated with the reactive ester of haloacylacetic acid, which wasconverted to its oxime, followed by cyclization with thiourea anddeprotection of the ester group to afford cefdinir. The product obtainedby the process described in examples 14 and 16 is approximately 80–85%pure. The cyclization step suffers from poor yield and affords brownishcolor of the thiazole derivative, which subsequently affords cefdinir,but quality and yield were inferior. Further, owing to the fact that theexpensive 7-amino-3-vinyl-3-cephem-4-carboxylic acid is carried throughfour steps, cost of producing cefdinir is high.

U.S. Pat. No. 4,935,507 claims the novel crystalline form of thecefdinir syn-isomer and a process for preparing the same. The X-raycrystallography data given in this patent is given in the followingtable:

2 θ ° Values Relative Intensity 14.7 76 17.8 56 21.5 100 22.0 70 23.4 3824.4 80 28.0 40The crystalline form (Crystal A) of U.S. Pat. No. 4,935,507 is preparedfrom the syn-isomer prepared according to the procedures described inExamples 14 and 16 of U.S. Pat. No. 4,559,334.

In our U.S. Pat. No. 6,388,070, we disclosed a process for preparing acompound of formula (VIII), wherein, R₁ represents H, trityl, etc., R₂represents H, phenyl, etc., R₃ represents CH₃, CH═CH₂, etc., R₄ is H ora salt or a carboxylic protecting group; R₅ is H or trimethylsilyl;comprising acylating the compound of formula (VI) with compound offormula (VII) in the presence of an organic solvent, organic base and asilylating agent at a temperature in the range of −10° C. to +30° C. Thereaction is shown in scheme II below:

U.S. Pat. No. 6,093,814 discloses a process for the preparation ofcefdinir and its intermediate as represented in Scheme III:

In this process p-methoxybenzyl 7-amino-3-vinyl-3-cephem-4-carboxylateis condensed with 2-mercaptobenzothiazolyl(Z)-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetate in N,N-dimethylacetamide, and the product obtained was treated with p-toluenesulfonicacid in the presence of a mixture of diethyl ether and methanol to getcrystalline7-[(2-amino-4-thiazolyl)-2-(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid.pTSA.2DMAc solvate. This process utilizes highly volatile,low-boiling and therefore industrially-not-preferred solvent, diethylether, for crystallizing out the above solvate. In addition, thequantity of the low-boiling solvent used is also very high ranging from60–100 volumes, thereby adding hazard to the operations. Added to thisis the fact that the recovery of these solvents from their mixture isnot straight-forward.

U.S. Pat. No. 6,350,869 discloses the purification of impure cefdinirthrough the preparation of N,N-dicyclohexylamine salt of7-[2-amino-4-thiazolyl-2-(z)-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid and subsequent hydrolysisto get pure cefdinir. This process requires the preparation of crudecefdinir, conversion to N,N-dicyclohexylamine salt and then hydrolysisof the salt to get pure cefdinir, and therefore the overall yield is notattractive.

U.S. Pat. No. 6,350,869 also emphasizes that cefdinir is unstable in thepresence of other amines, with which, it gets heavily degraded. Inaddition, Yoshihiko Okamoto et al. (J. Pharm. Sci. Vol. 8(9), 976, 1996)report that cefdinir may be unstable under basic environment.

Crystalline cefdinir has limitations in formulation development as itcannot be developed into tablets.

Considering the foregoing limitations, we undertook an investigation inour lab to develop a product which is easy to handle and convenient todevelop a dosage which is easily absorbable. We also parallel undertookan investigation to identify a process, which involves (i) less numberof steps, (ii) the direct isolation of cefdinir, with out the need toprepare crude cefdinir in an additional step. This would permitcommercializing the production of high-pure cefdinir withindustrial-friendly solvent, which can further be recovered forrecycling.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to provide a novelamorphous monohydrate of cefdinir which has very good bioavailabilityand useful in developing different dosage forms.

Another objective of the present invention is to provide a commerciallyviable process for the preparation of cefdinir and novel amorphousmonohydrate of cefdinir of the formula (I), which would be easy toimplement on manufacturing scale.

Yet another objective of the present invention is to provide new saltsof formula (XIV), which are insoluble and stable throughout the processof producing the cefdinir and a process for the preparation of cefdinirusing these new salts.

SUMMARY OF THE INVENTION

In an embodiment of the present invention, there is provided process forthe preparation of cefdinir of the formula (I)

comprising the steps of:

-   i) condensing 7-amino-3-cephem-4-carboxylic acid of the    formula (XII) wherein R₁ is as defined above with compound of the    formula (XIII) in the presence of a tertiary amine and an organic    solvent, followed by treatment with a base to produce a salt of    compound formula (XIV), wherein M⁺ is a counter ion and-   ii) hydrolyzing the compound of the formula (XIV) using an acid in    the presence of a solvent to produce cefdinir of formula (I).    The reaction is shown in scheme-IV below:

Another embodiment of the present invention provides a novel amorphousmonohydrate of cefdinir of the formula (I).

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel amorphous monohydrate of cefdinirof the formula (I) comprising hydrolyzing the compound of the formula(XV)

comprising the steps of:

-   i) adding an organic solvent to compound of formula (XV),-   ii) adjusting the pH of the resulting solution using an acid at a    temperature in the range of 10 to 40° C.,-   iii) cooing the resulting solution rapidly to −40 to 0° and-   iv) isolating the novel amorphous monohydrate of cefdinir of the    formula (I).

In yet another embodiment of the present invention, there is provided aprocess for the preparation of novel amorphous monohydrate of cefdinirof the formula (I) comprising hydrolyzing the compound of the formula(XV)

comprising the steps of

-   i) adding an organic solvent to compound of formula (XV),-   ii) cooing the resulting solution to −40 to 0° and-   iii) adjusting the pH of the resulting solution by rapid addition of    an acid at a temperature in the range of 10 to 40° C.,-   iv) isolating the novel amorphous monohydrate of cefdinir of the    formula (I).

DESCRIPTION OF FIGURES

FIG. 1: Comparison of powder XRD pattern of the sample preparedaccording to U.S. Pat. No. 4,935,507 and the sample prepared accordingto example 3 and example 4.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, the activation grouprepresented by X is selected from ester, thioester, halogen atom such aschlorine, bromine, iodine,

where R₆ represents (C₁–C₄)alkyl group such as methyl, ethyl, n-propyl,iso-propyl, n-butyl or iso-butyl or a phenyl group; Alk group represents(C₁–C₄)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butylor iso-butyl.

In an other embodiment of the present invention, the counter ionrepresented by M is selected from sodium, potassium, lithium, magnesium,ammonium, dicyclohexylamine, N,N′-dibenzylethylenediamine,1,8-diazabicyclo(5.4.0)undec-7-ene (DBU),1,5-diazabicyclo(4.3.0)non-5-ene, N,N′-diphenylethylenediamine,1,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine,N,N-diisopropylamine and the like.

In another embodiment of the present invention, the tertiary amine usedfor condensation in step (i) is selected from triethylamine,N-methylpiperidine, N,N-diisopropylethylamine, trimethylamine and thelike.

In yet another embodiment of the present invention, the organic solventused for condensation in step (i) is selected from ethanol, methanol,isopropanol, THF, cyclohexanol, acetone, butan-2-one, acetonitrile,DMAc, water or a mixture thereof.

In yet another embodiment of the present invention, the base used forcondensation in step (i) is selected from sodium hydroxide, sodiumacetate, sodium 2-ethyl hexanoate, potassium hydroxide, ammoniumhydroxide, ammonium acetate, calcium hydroxide, dicyclohexyl amine,N,N′-dibenzylethylenediamine diacetate,1,8-diazabicyclo(5.4.0)undec-7-ene (DBU),1,5-diazabicyclo(4.3.0)non-5-ene, N,N′-diphenylethylenediamine,1,4-diazabicyclo(2.2.2)octane, N,N-diisopropylethylamine,N,N-diisopropylamine, and the like.

In yet another embodiment of the present invention, the organic solventused for hydrolysis is selected from acetone, 2-butanone, methanol,isopropanol, ethanol, THF, acetonitrile, DMAc, water and the like ormixtures thereof.

In another embodiment of the present invention, the hydrolysis iscarried out using acid selected from HCl, sulfuric acid, formic acid,acetic acid, aromatic/aliphatic sulfonic acids such as benzenesulfonicacid, p-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonicacid, triflic acid, and the like.

In yet another embodiment of the present invention, the compound offormula (I) obtained is a syn isomer.

The present invention is based on the observation that rapid cooling ofthe aqueous solvent solution of cefdinir to low temperatures and addingthe acid rapidly produces amorphous cefdinir. The technique can beachieved either by cooling the aqueous solvent solution to lowtemperatures and adding the acid rapidly to adjust the pH to precipitatethe amorphous product or adding the acid to adjust the pH and rapidlycooling the resultant solution to precipitate the amorphous product.

In yet another embodiment of the present invention, there is providednew salts of compounds of formula (XIV)

wherein M⁺ represents a counter ion as defined above.

The foregoing technique has been found to be markedly attractive, bothfrom commercial point of view, as well as from manufacturing viewpointand affords good quality of amorphous cefdinir of the formula (I).

Many other beneficial results can be obtained by applying disclosedinvention in a different manner or by modifying the invention with thescope of disclosure.

The present invention is illustrated with the following examples, whichshould not be construed as limiting to the scope of the invention.

EXAMPLE 1

Step (i)

Preparation of2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(trityloxyimino)acetate

To an ice-cold suspension of(Z)-(2-aminothioazol-4-yl)-2-(trityloxyimino)acetic acid (25 gm) intetrahydrofuran (200 ml), triethylamine (10 gm) was added dropwise over10 minutes at 0–5° C. Bis-(2-oxo-oxazolidinyl)phosphinic chloride (15.4gm) was added and stirred for one hour at 0–5° C. To the reactionmixture 2-mercapto-5-phenyl-1,3,4-oxadiazole (9.8 gm) and triethylamine(5.0 gm) was added dropwise over 15 minutes and stirred at 0–5 ° C. for6–7 hours. After completion of reaction, chilled water (500 ml) wasadded at 10–20° C. in 30–40 minutes and stirred at 20° C. for 2 hours.Then the slurry was cooled to 5–10° C. and stirred at this temperaturefor 45 minutes. The product thus obtained was filtered washed with water(100 ml) and dried at 30–35° C. for 4–5 hours to yield the titlecompound (50 gm, water content is 40%).

Step (ii)

Preparation of potassium7β-[2-(2-amino-4-thiazolyl)-2-(Z-trityloxyimino)acetamido]-3-vinyl-3-vinyl-3-cephem-4-carboxylate

To a chilled suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid(25 gm) and2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(trityloxyimino)acetate(155 gm, water content is 40%) in N,N-dimethylacetamide (150 ml),triethylamine (23 gm) was added drop-wise at 10±2° C. over 30–45 minutesand the resulting mixture was stirred at 20±2° C. for 6–8 hours. Thereaction was monitored by HPLC. After completion of the reaction,tetrahydrofuran (125 ml), 10% sodium chloride solution (250 ml) andethyl acetate (250 ml) were added at 25° C. and stirred for 20 min. Theaqueous layer was separated and washed with ethyl acetate (250 ml). Tothe aqueous layer, ethyl acetate (500 ml) was added, cooled to 10–15°C., and the pH was adjusted to 2.8–3.0 by 1:1 HCl in 30 min. The layerswere separated and to the ethylacetate layer, 12% (w/v) methanolicpotassium hydroxide solution (60 ml) was added dropwise in 30 min at 25°C., and stirred for 45 min. The resulting slurry was filtered, washedwith ethyl acetate (150 ml) followed by acetone (150 ml) and dried at30–35° C. under vacuum to obtain the title compound (45 gm, HPLCPurity>99.0%).

Step (iii)

Preparation of7β-[2-(2-amino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid

A mixture of potassium7β-[2-(2-amino-4-thiazolyl)-2-(Z-trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate(25 gm) and activated carbon (2.5 gm) was added to an aqueous acetonesolution (1:1, 70 ml) containing p-toluenesulphonic acid (17.7 gm) at50° C. The reaction mixture was heated to 70° C. in 20 minutes andmaintained at this temperature for 35 minutes. After completion of thereaction, chilled ethylacetate (200 ml) having temperature −15° C. wasadded to the reaction mixture to reduce the temperature to 30–35° C. Thecarbon was filtered and the carbon bed was washed with water (50 ml).The filtrate was diluted with water (200 ml), warmed to 35° C. and pH ofthe solution was adjusted to 6.0–6.5 using aqueous ammonia solution(20%). The aqueous layer was separated and treated with carbon (2.0 gm)at 35° C. for 35 min. The carbon was filtered and the carbon bed waswashed with water (50 ml). Acetone (25 ml) was added to the filtrate and10% (w/v) solution of sulphuric acid was added dropwise to bring downthe pH from 4.5 to 2.8 at 33–35° C., stirred for 30 minutes and adjustedthe pH again to 2.6. The resulting slurry was stirred for 15–20 minutesat 33–35° C., cooled to 20–25° C., and stirred for 30 minutes. Theproduct thus obtained was filtered, washed with water (50 ml) and driedat 35° C. under vacuum for 3–4 hours to get the title compound (9.0 gm,HPLC purity>99%).

EXAMPLE 2

Step (i)

Preparation of2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(trityloxyimino)acetate

To an ice-cold suspension of(Z)-(2-aminothioazol-4-yl)-2-(trityloxyimino)acetic acid (25 gm) intetrahydrofuran (200 ml), triethylamine (10 gm) was added dropwise over10 minutes at 0–5° C. Bis-(2-oxo-oxazolidinyl)phosphinic chloride (15.4gm) was added and stirred for one hour at 0–5° C. To the reactionmixture 2-mercapto-5-phenyl-1,3,4-oxadiazole (9.8 gm) and triethylamine(5.0 gm) was added dropwise over 15 minutes and stirred at 0–5° C. for6–7 hours. After completion of reaction, chilled water (500 ml) wasadded at 10–20° C. in 30–40 minutes and stirred at 20° C. for 2 hours.Then the slurry was cooled to 5–10° C. and stirred at this temperaturefor 45 minutes. The product thus obtained was filtered washed with water(100 ml) and dried at 30–35° C. for 4–5 hours to yield the titlecompound (50 gm, water content is 40%).

Step (ii)

Preparation of potassium7β-12-(2-amino-4-thiazolyl)-2-(Z-trityloxyimino)acetamidol-3-vinyl-3-3-vinyl-3-cephem-4-carboxylate

To a chilled suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (5gm) and2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(trityloxyimino)acetate(24.2 gm) in tetrahydrofuran (40 ml) and water (5 ml), triethylamine(4.6 gm) was added drop-wise at 20±2° C. over 10–15 minutes and theresulting mixture was stirred at 30±2° C. for 6–8 hours. The progress ofthe reaction was monitored by HPLC. After completion of reaction,ethylacetate (100 ml) and water (75 ml) were added at 30±9° C. andstirred for 20 min. The aqueous layer was separated and washed withethyl acetate (75 ml). To the aqueous layer, ethylacetate (150 ml) wasadded, cooled to 10–15° C., and the pH was adjusted to 2.8–3.0 by 1:1HCl solution in 25–30 min. To the separated ethylacetate layer, acetone(50 ml) and a methanolic potassium hydroxide solution (7.5% w/v, 20 ml)were added dropwise in 25–30 min at 25–27° C. and stirred for further 45min. The resulting slurry was filtered, washed with acetone (2×25 ml)and dried at 30–35° C. under vacuum to obtain the title compound (5.0gm, HPLC Purity>99.0%).

Step (iii)

Preparation of7β-[2-(2-amino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid

A mixture of potassium7β-[2-(2-amino-4-thiazolyl)-2-(Z-trityloxyimino)acetamido]-3-vinyl-3(25gm) and activated carbon (2.5 gm) was added to an aqueous acetonesolution (1:1, 70 ml) containing p-toluenesulphonic acid (17.7 gm) at50° C. The reaction mixture was heated to 70° C. in 20 minutes andmaintained at this temperature for 35 minutes. After completion of thereaction, chilled ethylacetate (200 ml) having temperature −15° C. wasadded to the reaction mixture to reduce the temperature to 30–35° C. Thecarbon was filtered and the carbon bed was washed with water (50 ml).The filtrate was diluted with water (200 ml), warmed to 35° C. and pH ofthe solution was adjusted to 6.0–6.5 using aqueous ammonia solution(20%). The aqueous layer was separated and treated with carbon (2.0 gm)at 35° C. for 35 min. The carbon was filtered and the carbon bed waswashed with water (50 ml). Acetone (25 ml) was added to the filtrate and10% (w/v) solution of sulphuric acid was added dropwise to bring downthe pH from 4.5 to 2.8 at 33–35° C., stirred for 30 minutes and adjustedthe pH again to 2.6. The resulting slurry was stirred for 15–20 minutesat 33–35° C., cooled to 20–25° C., and stirred for 30 minutes. Thecrystals thus obtained was filtered, washed with water (50 ml) and driedat 35° C. under vacuum for 3–4 hours to get the title compound (9.0 gm,HPLC purity<99%).

EXAMPLE 3 Preparation of(Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid in amorphous hydrate form

Ammonium(Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4carboxylate(20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) andwarmed to 33–35° C. This aqueous solution was treated with activatedcharcoal and EDTA at 35° C. for 40 minutes. The carbon was filtered andthe carbon bed was washed with water (70 ml). This aqueous acetonesolution was cooled to −30° C. and a (10%) solution of aqueous sulphuricacid was added rapidly, stirred for 30 minutes and warmed to 0–2° C. Theproduct thus obtained was filtered at 0–2° C., washed with cold-water(100 ml) and dried at 40–45° C. under vacuum for 5–6 hours to get(Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (6.0 gm, HPLC quality 89.0%, water content 4–5%).

EXAMPLE 4 Preparation of(Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid in amorphous hydrate form

Ammonium(Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic(20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) andwarmed to 33–35° C. This aqueous solution was treated with activatedcharcoal and EDTA at 35° C. for 40 minutes. The carbon was filtered andthe carbon bed was washed with water (70 ml). The pH of this aqueousacetone solution was adjusted to 0.6 at 33–35° C. using a (10%) solutionof aqueous sulphuric acid. This solution was cooled rapidly to −10° C.and stirred for 30 minutes. The product thus obtained was filtered at−10° C., washed with cold-water (100 ml) and dried at 40–45° C. undervacuum for 5-6 hours to get(Z)-7β-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylicacid (6.0 gm, HPLC quality 93.0%, water content 4–5%).

1. A process for the preparation of cefdinir of the formula

comprising: i) condensing 7-amino-3-cephem-4-carboxylic acid of theformula (XII):

wherein R₁ is as defined above, with a compound of the formula (XIII):

where X represents an activation group, in the presence of a tertiaryamine and a solvent, wherein the solvent is selected from the groupconsisting of organic solvents and water, followed by treatment with abase to produce a salt of compound formula (XIV):

wherein M⁺is a counter ion; and ii) hydrolyzing the compound of theformula (XIV) using an acid in the presence of a solvent to producecefdinir of formula (I).
 2. The process according to claim 1, wherein Xis selected from the group consisting of a chlorine atom, a bromineatom,

where R6 represents a (C1–C4)alkyl group or a phenyl group and Alkrepresents a (C1–C4) alkyl.
 3. The process according to claim 1, whereinthe counter ion represented by M is selected from the group consistingof sodium, potassium, lithium, magnesium, ammonium,dicyclohexylanimonium, N,N-diisopropylethylammonium, andN,N-diisopropylammomum.
 4. The process according to claim 1, wherein thetertiary amine is selected from the group consisting of triethylamine,N-methylpiperidine, N,N-diisopropylethylamine, and trimethylamine. 5.The process according to claim 1, wherein the solvent used in step (i)is selected from the group consisting of ethanol, methanol, isopropanol,THF, cyclohexanol, acetone, butan-2-one, acetonitrile, DMAc, water, andmixtures thereof.
 6. The process according to claim 1, wherein thesolvent used in step (ii) is selected from the group consisting ofacetone, 2-butanone, methanol, isopropanol, ethanol, THF, acetonitrile,DMAc, water, and mixtures thereof.
 7. The process according to claim 1,wherein the acid is selected from the group consisting of HC1, sulfuricacid, formic acid, acetic acid, and aromatic/aliphatic sulfonic acids.8. The process according to claim 1, wherein the compound of formula (Dobtained is a syn isomer.
 9. A process for the preparation of a novelamorphous monohydrate of cefdinir represented by formula (I):

comprising: hydrolyzing the compound represented by formula (XV):

wherein M⁺represents a counter ion, comprising the steps of: i) adding asolvent to a compound of formula (XV), wherein the solvent is selectedfrom the group consisting of organic solvents and water, ii) adjustingthe pH of the resulting solution using an acid at a temperature in therange of 10 to 40° C., iii) cooling the resulting solution rapidly to−40 to 0° C., and iv) isolating the novel amorphous monohydrate ofcefdinir represented by formula (I).
 10. A process for the preparationof novel amorphous monohydrate of cefdinir represented by formula (I):

comprising: hydrolyzing the compound represented by formula (XV)

comprising the steps of: i) adding a solvent to a compound of formula(XV), wherein the solvent is selected from the group consisting oforganic solvents and water, ii) cooling the resulting solution to −40 to0°C. and iii) adjusting the pH of the resulting solution by rapidaddition of an acid at a temperature in the range of 10 to 40°C., andiv) isolating the novel amorphous monohydrate of cefdinir represented byformula (I).
 11. The process according to claim 9, wherein the solventis selected from the group consisting of acetone, 2-butanone, methanol,isopropanol, ethanol, THF, acetonitrile, DMAc, water and mixturesthereof.
 12. The process according to claim 9, wherein the acid isselected from the group consisting of HC1, sulfuric acid, formic acid,acetic acid, and aromatic/aliphatic sulfonic acids.
 13. A compound ofcompound formula (XIV),

wherein M⁺ represents a counter sodium ion or potassium ion.